2026-06-14T05:06:02Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/85712024-11-29T22:32:00Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Morando, Maria Agnese author Saladino, Giorgio author D'Amelio, Nicola author Pucheta-Martinez, Encarna author Lovera, Silvia author Lelli, Moreno author López-Méndez, Blanca author Marenchino, Marco author Campos Olivas, Ramon author Gervasio, Francesco Luigi author 2016-04-18 Understanding the conformational changes associated with the binding of small ligands to their biological targets is a fascinating and meaningful question in chemistry, biology and drug discovery. One of the most studied and important is the so-called "DFG-flip" of tyrosine kinases. The conserved three amino-acid DFG motif undergoes an "in to out" movement resulting in a particular inactive conformation to which "type II" kinase inhibitors, such as the anti-cancer drug Imatinib, bind. Despite many studies, the details of this prototypical conformational change are still debated. Here we combine various NMR experiments and surface plasmon resonance with enhanced sampling molecular dynamics simulations to shed light into the conformational dynamics associated with the binding of Imatinib to the proto-oncogene c-Src. We find that both conformational selection and induced fit play a role in the binding mechanism, reconciling opposing views held in the literature. Moreover, an external binding pose and local unfolding (cracking) of the aG helix are observed. Sci Rep. 2016;6:24439. 10.1038/srep24439 2045-2322 2045-2322 Scientific reports 27087366 http://hdl.handle.net/20.500.12105/8571 Conformational Selection and Induced Fit Mechanisms in the Binding of an Anticancer Drug to the c-Src Kinase